Method for preparing biodegradable polyester and itself prepared thereby

ABSTRACT

Disclosed is a method for preparing a biodegradable polymer in the form of uniform powder or spherical particles by dispersion polymerization without a grinding step. The method for preparing a biodegradable polyester includes dispersing a monomer in the presence of a catalyst in a dispersion solvent to form a solid or liquid phase for dispersion polymerization and thereby to yield a biodegradable aliphatic polyester in the form of spherical particles or powder, the monomer comprising a mixture of a first compound (e.g., lactide or glycolide) and a second compound being selected from the group consisting of polyhydric alcohols (e.g., glycerin, erythritol, penterythritol or dipentaerythritol) and carprolactone. The present invention readily prepares a biodegradable polymer having a high molecular weight in the form of uniform powder or spherical particles.

TECHNICAL FIELD

[0001] The present invention relates to a method for preparingbiodegradable polyester and itself prepared thereby. More particularly,the present invention relates to a method for preparing biodegradablepolymer in the form of spherical or amorphous formless particles orpowder by polymerizing a monomer in the non-solvent condition for themonomer at a temperature below the melting point of the polymer.

BACKGROUND ART

[0002] Biodegradable polymers are now attracting considerable attention,due to their peculiar characteristics related to degradability, invarious fields of industry such as medical, agricultural andenvironmental fields and being considered to be of a great valueparticularly in the medical and environmental fields.

[0003] Biodegradable polymers are largely classified into naturalbiodegradable polymers and synthetic biodegradable polymers. Naturalbiodegradable polymers synthesized from naturally occurring substancesare very environment-friendly and excellent in physical performance andbiological adaptability. But the natural biodegradable polymers are veryexpensive and uncontrollable in regard to properties, since they areoriginated from natural substances.

[0004] On the other hand, synthetic biodegradable polymers are recentlyconsidered to be of a great commercial value because they arecontrollable in properties, unlike natural biodegradable polymers.

[0005] Among the synthetic biodegradable polymers, polyglycolide (PGA)and polylactide (PLA) are particularly excellent in performance andapplied for various uses in the medical field due to theirenvironment-friendliness and innoxiousness to living bodies. Forexample, they have been developed and used for DDS (Drug DeliverySystem), bone- or tissue-fixing pins, screws or stitching fibers, and soforth.

[0006] But the solid process of these polymers may result innon-uniformity of properties, deterioration of workability.Particularly, the polymers prepared in the massive solid state are to begrinded in proper size prior to a forming process, and the polymergrinding step is difficult to perform in the case of mass production ona commercial scale.

[0007] For some uses, such as DDS, the polymers are to be controllablein the type and size of particles for the sake of controlling therelease rate of drugs. To solve this problem, many studies have beenmade on the preparation methods for minutely controlling thedissolution-extraction process of the polymer using solvent andnon-solvent conditions, for example, by SAS (Supercritical Anti-Solvent)method. But these preparation methods are incomplete in that the polymeris uncontrollable in molecular weight and particle size and theproduction yield is extremely low.

DISCLOSURE OF INVENTION

[0008] It is therefore an object of the present invention to solve theproblems with the prior art and to provide a novel method for preparingbiodegradable polymer, such as polylactide (PLA), polyglycolide (PGA) orpolycaprolactone (PCL), in the form of spherical particles or the likedirectly by dispersion polymerization without a grinding step.

[0009] It is another object of the present invention to provide a methodfor readily preparing biodegradable polymer particles for medical usessuch as DDS with high yield.

[0010] To achieve the objects of the present invention, there isprovided a method for preparing a biodegradable polyester that includesdispersing monomer in the presence of a catalyst in a dispersion solventto form a solid or liquid phase for dispersion polymerization andthereby to yield a biodegradable aliphatic polyester in the form ofspherical particles or powder, the monomer comprising a mixture of acompound (A) represented by the following formula I and a compound (B)being selected from the group consisting of compounds represented by thefollowing formulas II to V and caprolactones:

[0011] [Formula I]

[0012] wherein R1 and R2 are a hydrogen or a C₁-C₄ alkyl group;

HO—C(═O)—(CH₂)_(n)—(O═)C—OH  [Formula II]

[0013] wherein n is 1 to 8:

H—O—(CH₂)_(m)—O—H  [Formula III]

[0014] wherein m is 2 to 8;

R³(OH)_(x)  [Formula IV]

[0015] wherein x is 2 to 6; and R3 is a saturated C₁-C₈ hydrocarbon oran ether (—R—O—R—); and

H—O—{(CH₂CH₂)_(y)O}_(z)—H  [Formula V]

[0016] The content of the compound (A) in the monomer is preferably atleast 75 mol %, more preferably at least 85 mol %, and the content ofthe compound (B) is preferably less than 25 mol %, more preferably lessthan 15 mol %.

[0017] Preferably, the compound (A) is lactides or glycolides, and thecompound (B) of formula(V) is polyhydric alcohols, for example,glycerin, erythritol, pentaerithritol or dipentaerithritol, etc.

[0018] The preferred dispersion solvent as used herein should meet thefollowing requirements:

[0019] (1) to be an organic compound in which the polymer has nosolubility;

[0020] (2) to be an organic compound in which the monomer has asolubility of less than 5%;

[0021] (3) to be chemically inert with the monomer;

[0022] (4) to have a viscosity of 1 to 300 cSt at 25° C.; and

[0023] (5) to have a lower specific density of 0.85 to 1.25 than thepolymer. Examples of the preferred dispersion solvent may includealkyl/aryl-substituted siloxane compounds (e.g., poly(dimethylsiloxane),poly(phenyl-methylsiloxane), etc.) and long-chained saturatedhydrocarbons (e.g. liquid paraffin).

[0024] The polymerization temperature is preferably between the meltingpoint T_(m) of the polymer and the higher temperature out of the meltingpoint T_(m) of the monomer and the glass transition temperature T_(g) ofthe polymer. More preferably, the polymerization temperature is in therange of ⅓ to ⅔ between the melting point of the polymer and the highertemperature of the melting point of the monomer and the glass transitiontemperature of the polymer.

[0025] Preferably, the polymerization is performed under vacuum or inthe inert gas atmosphere.

[0026] The catalyst is added directly to the monomer or preferably tothe medium for the sake of enhancing the uniformity of the particle sizeand the polymerization degree.

[0027] Now, the present invention will be described in further detailwith reference to the accompanying drawings.

[0028] The present invention comprises a method for preparing abiodegradable polymer having a weight average molecular weight of atleast 10,000 to 500,000 in the form of spherical or amorphous particlesor powder by polymerizing a monomer in non-solvent or poor solventconditions at a temperature lower than the melting point of thecorresponding polymer.

[0029] The present invention is directed to a method for preparing abiodegradable polymer that comprises a copolymer of a homopolymer of onemonomer (A) represented by the following formula I with a compound (B)selected from the compounds represented by the following formulas II toV and caprolactones:

[0030] [Formula I]

[0031] wherein R1 and R2 are a hydrogen or a C₁-C₄ alkyl group;

HO—C(═O)—(CH₂)_(n)—(O═)C—OH  [Formula II]

[0032] wherein n is 1 to 8;

H—O—(CH₂)_(m)—O—H  [Formula III]

[0033] wherein m is 2 to 8;

R³(OH)_(x)  [Formula IV]

[0034] wherein x is 2 to 6; and R3 is a saturated C₁-C₈ hydrocarbon oran ether (—R—O—R—); and

H—O—{(CH₂CH₂)_(y)O}_(z)—H  [Formula V]

[0035] More specifically, the present invention relates to thepreparation of a biodegradable homopolymer or copolymer comprising atleast 75 mol %, more preferably 85 mol % of the monomer component (A)and less than 25 mol %, more preferably 15 mol % of the monomercomponent (B).

[0036] The specific examples of the compound of the formula I mayinclude lactide and glycolide. These compounds, i.e., lactide andglycolide are in most cases obtained in a racemic mixture of D- andL-forms depending on the bonding types of R1 and R2. Preferably, themonomers as used in the present invention preferably contain at least85% of D- or L-form.

[0037] In the present invention, the dispersion solvent completelydehydrated is added to the reactor and then the monomer is added in theform of powder or in the melted state. The ratio of the monomer to thedispersion solvent is in the range of 10 to 80% (w/v), more preferably30 to 70% (w/v). When the ratio of the monomer to the dispersion solventis less than 10% (w/v), the polymer can be prepared in the form ofpowder but a large amount of the dispersion solvent is used per unitweight of the polymer, which is undesirable in the aspect of economy.The content of the monomer exceeding 80% deteriorates the dispersabilityof the monomer in the dispersion solvent, as a result of which thepolymer aggregates together in the process of the polymerizationreaction and the polymer having a low crystallinity sticks on the innerwall of the reactor due to the shear force caused by stirring. Theseproblems prevent the production of polymers in the form of sphericalparticles or powder in uniform size.

[0038] As for the requirements of the dispersion solvent, the dispersionsolvent should show neither of solubility to the polymer nor chemicalreaction that may adversely affect the polymerization reaction, such asa change in the chemical structure of the monomer or the bonding to themonomer.

[0039] A slight amount of the polymer soluble in the dispersion solventcan prevent the formation of the polymer in the dispersion solvent. Thepolymer is further dissolved in the dispersion solvent to form asolution with the progress of the polymerization reaction, changing theviscosity and increasing the molecular weight. As a result, polymerparticles aggregate together without formation of uniform particles.

[0040] Furthermore, when the cyclic monomer reacts with the dispersionsolvent to form a compound, tile reactants are deteriorated in purity torapidly lower the polymerization reactivity and polymers of a highmolecular weight cannot be produced.

[0041] Other properties suggested as requirements of the dispersionsolvent are solubility of the monomer in the dispersion solvent,viscosity and specific density.

[0042] The solubility of the monomer in the dispersion solvent isdesirably low as less than 5%. When the solubility is high, solutionpolymerization prevails over dispersion polymerization (i.e., suspensionpolymerization or emulsion polymerization), making it difficult to formpolymer particles and limiting the degree of polymerization.

[0043] The viscosity of the dispersion solvent is preferably 1 to 300cSt at 25° C. When the viscosity is out of this range, there is aproblem in realizing uniform dispersion due to an extremely largedifference in viscosity between the dispersion solvent and the meltedmonomer, and the size and form of polymer particles cannot becontrolled.

[0044] The specific density of the dispersion solvent is preferably inthe range of from 0.85 to 1.25 at 25° C. When the specific density isless than 0.85, the melted monomer is settled in the dispersion solventand scarcely dispersed uniformly even with vigorous agitation, as aresult of which the polymer cannot be obtained in the form of uniformparticles. Otherwise when the specific density of the dispersion solventis greater than 1.25, or exceeds that of the polymer to be produced, thepolymer as well as the monomer is floated on the surface of thedispersion solvent to prevent effective mixing.

[0045] Now, a description will be given to the method for preparing apolymer using a dispersion solvent and a monomer according to thepresent invention.

[0046] After the addition of the dispersion solvent and the monomer, thereactor is sealed up and connected to a vacuum pump to form vacuum forat least one hour and thereby to remove air, oxygen, water andimpurities other than polymers from the dispersion solvent and themonomer. The polymerization reaction is performed under vacuum or in theinert gas atmosphere, including the nitrogen atmosphere, which is toprevent introduction of dissolved oxygen and water that may otherwiseinhibit the increase in the degree of polymerization.

[0047] Following the removal of impurities under vacuum, the reactantsare heated to a temperature above the melting point of the monomer andstirred to disperse the melted monomer in the form of droplets in thedispersion solvent. The mixing speed should be controlled properly inconsideration of the fact that the dispersion solvent and the monomerare not mixed but separated into two phases due to the difference ofspecific gravity. When the mixing speed is too high, the shear forceforms a stream of the monomer having a higher specific gravity on theinner wall of the reactor or the centrifugal force sticks the monomer onthe inner wall of the reactor. At an extremely low mixing speed, themonomer solution of the higher specific gravity is settled to lower thedispersion effect and to prevent formation of uniform droplets. Thus themixing speed is to be properly controlled depending on the size or shapeof the reactor such that the melted monomer can circulate stably in thedispersion solvent.

[0048] The polymerization temperature is dependent on the type of themonomer and on whether the polymerization reaction is homopolymerizationor copolymerization. The optimal temperature is preferably determinedbetween the melting point (crystal transition temperature) of thepolymer and the higher temperature of the melting point T_(m) of themonomer and the glass transition temperature of the polymer. Morepreferably, the polymerization temperature is in the range of ⅓ to ⅔between the melting point of the polymer and the higher temperature ofthe melting point of the monomer and the glass transition temperature ofthe polymer.

[0049] A catalyst is added when the monomer solution is uniformlydispersed in the dispersion solvent and the temperature reaches theoptimal polymerization temperature. The catalyst in the liquid state maybe added directly as the formulated concentrate, or previously dissolvedor dispersed in a solvent such as toluene, ethyl acetate or hexane orthe dispersion solvent for polymerization. In some cases, the catalystcan be added directly to the monomer. The catalyst for the biodegradablepolymer to be prepared in the present invention is variable and, as wellknown in the art, the polymerization is performed through variousmechanisms according to the type of the catalyst used.

[0050] Zn—, Sn— or Al-based organic metallic catalysts are typicallyused as the catalyst. Specific examples of the organic metallic catalystmay include: Sn-based catalysts (e.g., stannic chloride, stannous oxide,stannous octoate, stanlous chloride dihydrate, tetraphenyl tin, etc.);Zn-based catalysts (e.g., zinc powder, diethyl zinc, zinc octoate, zincchloride, zinc oxide, etc.); and Al-based catalysts (e.g., aluminumchloride, aluminum ethoxide, etc.). Among these catalysts, stannousoctoate and aluminum chloride are preferred.

[0051] In the present invention, the molecular weight of the polymer canbe controlled by the added amount of the catalyst, the polymerizationtemperature and the polymerization time. Among these factors, the addedamount of the catalyst is most important in the control of the molecularweight.

[0052] In the present invention, the polymer can be obtained in the formof uniform spherical particles (0.5 to 100 μm in particle size) when theviscosity of the dispersion solvent is lower than that of the monomer;or in the form of amorphous particles when the viscosity of thedispersion solvent is equal to or higher than that of the monomer.

[0053] Furthermore, in the present invention, the size of the polymerparticles thus produced is mainly dependent on the mixing speed and thesolid content, and the final yield after the complete removal of theunreacted monomer amounts to 90 to 95%.

BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Further objects and advantages of the invention can be more fullyunderstood from the following detailed description taken in conjunctionwith the accompanying drawing in which:

[0055]FIG. 1 is an SEM picture of the biodegradable polymer preparedaccording to an embodiment of the present invention;

[0056]FIG. 2 is an SEM picture of the biodegradable polymer preparedaccording to another embodiment of the present invention;

[0057]FIG. 3 is an SEM picture of the biodegradable polymer preparedaccording to further another embodiment of the present invention; and

[0058]FIG. 4 shows DSC (Differential Scanning Calorimetry) records ofthe biodegradable polymers prepared according to the examples of thepresent invention and the comparative examples.

BEST MODE FOR CARRYING OUT THE INVENTION

[0059] The present invention will now be described in detail by way ofthe examples of the present invention and the comparative examples.

EXAMPLE 1

[0060] 200 g of L-lactide as the monomer (A) and 500 ml ofpolydimethylsiloxane having a viscosity of 10 cSt as the dispersingsolvent were added to a flask and removed of air and impurities undervacuum. After melting L-lactide at a raised temperature of 130° C., 0.1g of stannous 2-ethyl hexanoate was added to the flask with vigorousstirring under vacuum for 24 hours of polymerization reaction. Thepolymer thus obtained in the powder form was washed with methanol andhexane several times and then dried at the room temperature under vacuumfor 24 hours.

[0061] The molecular weight of the polymer as determined by solutionviscosity method was reduced to a weight average molecular weightaccording to the “Mark-Houwink” equation that expresses the relationshipbetween intrinsic viscosity and molecular weight.

For linear polylactide (PLLA), [η]=4.41×10⁻⁴ ·M _(w) ^(0.72)(dl/g)

For star-like (branched) PLLA, [η]=2.04×10⁻⁴ ·M _(w) ^(0.72)(dl/g)

[0062] To determine the intrinsic viscosity [η], the reduced viscositywas measured with an Ubbelohde viscometer at 25° C. using a solution ofthe polymer in chloroform (0.05 to 0.5 g/dL) and then extrapolated by0%.

[0063] The final product, poly(L-lactide) was obtained in the form ofspherical particles having an average diameter of 10 μmas shown in FIG.1 with a weight average molecular weight of 420,000.

EXAMPLES 2 to 10

[0064] The procedures were performed in the same manner as described inExample 1, excepting that the monomer components (A) and (B) and thedispersion solvent were used with reference to Table 1. The molecularweight and the properties of the biodegradable polymers thus obtainedare presented in Table 1. TABLE 1 Examples 2 to 10 Dispersion mediumMonomer Monomer/ particle Ingredi- Ingredient B/ volume DispersionMolecular Size Δ H_(Tm) Re- ent A B (A + B) type viscosity (ml) mediumweight Shape (μm) (J/g) marks 2 LLA — 0% Polydimethylsiloxane 200 cSt 500 20% 370,000 amorphous 20 87.6 3 LLA — 0% Polyphenylmethylsiloxane 10cSt 500 10% 400,000 spherical 2 93.3 FIG. 4 © 4 LLA — 0%Polydimethylsiloxane 10 cSt 500 80% 740,000 spherical 70 81.0 5 LLA Er0.2%   Polydimethylsiloxane 10 cSt 500 60% 760,000 spherical 25 89.4 6LLA — 0% Liguid Paraffin 30 cSt 500 20% 480,000 spherical 110 76.6 7 GA— 0% Polydimethylsiloxane 10 cSt 500 40% 680,000 spherical 50 105 8 LAGA 20%  Polydimethylsiloxane 10 cSt 500 40% 560,000 spherical 15 56.1 9LLA CL 10%  Polydimethylsiloxane 10 cSt 500 10% 280,000 spherical 5 42.310 LLA Er, 5% Polydimethylsiloxane 10 cSt 500 40% 440,000 spherical 3547.8 SA, EG

COMPARATIVE EXAMPLES 1 AND 2

[0065] The procedures were performed in the same manner as described inExample 1, excepting that the monomer components (A) and (B) and thedispersion solvent were used with reference to Table 2. The molecularweight and the properties of the biodegradable polymers thus obtainedare presented in Table 2.

COMPARATIVE EXAMPLE 3

[0066] Bulk polymerization was performed only with the L-lactide monomeras listed in Table 2. TABLE 2 Comparative Example 1, 2 and 3 Dispersionmedium Monomer Monomer/ particle Ingredient Ingredient B/ vis- VolumeDispersion Molecular Size Δ H_(Tm) A B (A + B) type cosity (ml) mediumweight Shape (μm) (J/g) Remarks 1 LLA — 0% Polydimethylsiloxane 500 cSt500 40%  95,000 amorphous 0.5↓ 79.5 Yield (random - rate: shaped) below30%, difficult to collect 2 LLA — 0% Polydimethylsiloxane  10 cSt 50090% 250,000 — — 57.1 Impossible to form monomer drop(FIG. 4) 3 LLA — 0%590,000 39.1 Bulk polym- erization

[0067] As is apparent from the above examples and comparative examples,the preparation method of the present invention allows the preparationof biodegradable polyester particles with a high yield, while solvingthe problems with the conventional preparation methods that involve alow production yield with the difficulty in recovery of the product (inComparative Example 1) and a need for grinding and distribution steps soas to obtain workable particles (bulk polymerization in ComparativeExample 3).

[0068] The polymer obtained in Comparative Example 3, which shows anexample of bulk polymerization, has a lower crystallinity than thoseobtained in the examples of the present invention, as shown in Tables 1and 2. The heat of fusion Δ H_(Tm) is usually 40 to 60 J/g for bulkpolymerization and at least 80 J/g for emulsion polymerization.

Industrial Applicability

[0069] The present invention provides a very effective method forpreparing a biodegradable material having a high molecular weight in theform of homogeneous powder or spherical particles, which polymerparticles are useful for extrusion molding or solid-state extrusionmolding. The present invention also provides a preparation method thatallows the molecular weight and particle size of the polymercontrollable and thereby can be applied in different fields of industrysuch as pharmaceutical industry that requires polymer powder in the formof fine beads.

[0070] While the present invention has been described with reference tothe particular illustrative embodiments, it is not to be restricted bythe embodiments but only by the appended claims. It is to be appreciatedthat those skilled in the art can change or modify the embodimentswithout departing from the scope and spirit of the present invention.

What is claimed is:
 1. A method for preparing a biodegradable polyester,comprising: dispersing a monomer in the presence of a catalyst in adispersion solvent to form a solid or liquid phase for dispersionpolymerization and thereby to yield a biodegradable aliphatic polyesterin the form of spherical particles or powder, the monomer comprising amixture of a compound (A) represented by the following formula I and acompound (B) being selected from the group consisting of compoundsrepresented by the following formulas II to V and caprolactones:[Formula I]

wherein R1 and R2 are a hydrogen or a C₁-C₄ alkyl group;HO—C(═O)—(CH₂)_(n)—(O═)C—OH  [Formula II] wherein n is 1 to 8;H—O—(CH₂)_(m)—O—H  [Formula III] wherein m is 2 to 8;R³(OH)_(x)  [Formula IV] wherein x is 2 to 6; and R3 is a saturatedC₁-C₈ hydrocarbon or an ether (—R—O—R—); andH—O—{(CH₂CH₂)_(y)O}_(z)—H  [Formula V]
 2. The method as claimed in claim1, wherein the content of the compound (A) in the monomer is at least 75mol % and the content of the compound (B) is less than 25 mol %.
 3. Themethod as claimed in claim 1, wherein the content of the compound (A) inthe monomer is at least 85 mol % and the content of the compound (B) isless than 15 mol %.
 4. The method as claimed in claim 1, wherein thecompound (B) represented by the formula V is a polyhydric alcohol. 5.The method as claimed in claim 4, wherein the polyhydric alcohol isselected from the group consisting of glycerin, erythritol,pentaerythritol and dipentaerithritol.
 6. The method as claimed in claim1, wherein the dispersion solvent is an organic compound in which thepolymer has no solubility.
 7. The method as claimed in claim 1, whereinthe dispersion solvent is an organic compound in which the monomer has asolubility of less than 5%.
 8. The method as claimed in claim 1, whereinthe dispersion solvent is chemically inert with the monomer.
 9. Themethod as claimed in claim 1, wherein the dispersion solvent has aviscosity of 1 to 300 cST at 25° C.
 10. The method as claimed in claim1, wherein the dispersion solvent has a lower specific density of 0.85to 1.25 than the polymer.
 11. The method as claimed in claim 1, whereinthe dispersion solvent is an alkyl/aryl-substituted polysiloxanecompound or a long-chained, saturated hydrocarbon.
 12. The method asclaimed in claim 11, wherein the alkyl/aryl-substituted polysiloxanecompound is poly(dimethyl siloxane) or poly(phenylmethyl siloxane). 13.The method as claimed in claim 11, wherein the saturated hydrocarbon isliquid paraffin.
 14. The method as claimed in claim 1, wherein thepolymerization is performed at a polymerization temperature between themelting point (crystal transition temperature) of the polymer and thehigher temperature out of the melting point of the monomer and the glasstransition temperature of the polymer.
 15. The method as claimed inclaim 14, wherein the polymerization temperature is in the range of ⅓ to⅔ between the melting point (crystal transition temperature) of thepolymer and the higher temperature of the melting point of the monomerand the glass transition temperature of the polymer.
 16. The method asclaimed in claim 1, wherein the polymerization is performed under vacuumor in the inert gas atmosphere.
 17. The method as claimed in claim 1,wherein the catalyst is added to the dispersion solvent or to themonomer mixture during the polymerization process.
 18. A biodegradablepolyester in the form of spherical or amorphous(formless) particles orpowder as prepared by the method according to claim 1.